Guideline on efficacy and target animal safety for products supplied for use in minor species or for minor use under permit

1. Introduction

This is an outline of the Australian Pesticides and Veterinary Medicines Authority's (APVMA) target animal efficacy and safety data guidelines for veterinary chemical products intended for use in minor species or for minor use.

The Agvet Code Regulations defines minor use:

1. in relation to a chemical product or an active constituent, is a use of the product or constituent that would not produce sufficient economic return to an applicant for registration of the product to meet the cost of registration of the product, or the cost of registration of the product for that use, as the case requires (including, in particular, the cost of providing the data required for that purpose).

2. in relation to a chemical product, is a use of the product where the following apply:
   (a)  instructions for that use are in the Register in relation to one or more registered chemical products;
   (b)  none of those registered chemical products is available for sale anywhere in Australia.

We regard minor species for a particular purpose as being defined by exclusion, as any species other than major species. We regard major species for a particular purpose as being generally defined as cattle, horses, sheep, pigs, chickens, horses, dogs and cats.

Under state and territory prescribing laws, veterinarians may use APVMA-registered products ‘off label’, but take responsibility for product efficacy and safety to target animals, as well as the health and safety of people consuming produce from treated animals, people using the product, and the environment.

Off-label use is prescribing, using or authorising a client to use a registered drug or veterinary chemical in a manner outside the range of uses permitted by the approved label directions – including species of animal, dosage, treatment interval and so on. Veterinarians are permitted to exercise professional judgement in the off-label use or supply of most drugs or other veterinary medicines, but must not contravene a specific label restraint.

Where supply is to non-veterinarians, or for veterinarians intending to conduct an activity outside the scope of their state or territory prescribing rights, the information that may be submitted to the APVMA for the demonstration of efficacy and target animal safety will be influenced by whether the product is already registered by APVMA for use in another species or for another use in the registered species. The known pharmacological, toxicological and efficacy profile of an active constituent or a related active constituent may be used to support efficacy and target animal safety.

Where an active constituent has been approved by the APVMA or a product has been registered for a similar indication in another species, you may submit information relating to use in that species to support the application where scientifically justified. This approach may be used in lieu of conducting studies in the target species. For novel active constituents and for those where limited information is available relating to their use in any animal species, you should provide comprehensive information relating to use in the target species.

2. Scope

This guideline applies only to target animal efficacy and safety for pharmaceutical products. It excludes products for use in aquaculture and immunobiological products. When applying for minor use permits, applicants should also submit data or valid scientific argument to address the human health, environmental, and occupational health and safety aspects of the product as appropriate.

3. Legal basis

The statutory criteria that we must be satisfied of to issue a permit (with respect to safety, efficacy and trade) are the same as those required when registering a product. In addition to these legislative requirements, we maintain a policy that a permit is unlikely to be issued where there is a suitably registered product available for that purpose unless there is sufficient justification why a registered product cannot be used.

We may also consider advice from the APVMA Assessment, Investigation and Monitoring Team, holders, state and territory departments and the APVMA's Adverse Experience Reporting Program on claims of ineffectiveness of or adverse reaction to a registered product or in situations where the registered product is unavailable. This procedure ensures the permit system does not circumvent the normal registration processes. For extension of minor use permits, we will take into consideration use patterns and whether a suitable registered product has become available since the minor use permit was first issued.

4. Minor use permit for supply of products to veterinarians for use outside of veterinary prescribing rights

Permits for minor use may be issued where states or territories have limited such prescribing rights, for instance, to individual animals of a food-producing species. Where states or territories have limited such prescribing rights, we will, in consultation with those states or territories, consider granting a minor use permit for the treatment of a larger number of animals for a specified purpose.

A permit may be issued in instances where you can show that you are unable to provide comprehensive data on therapeutic effect because either:

• the indications for which the chemical product is intended are encountered so rarely that you cannot reasonably be expected to provide comprehensive evidence
• in the present state of scientific knowledge, comprehensive information cannot be provided

The permit may be issued subject to the following conditions:

• The chemical product in question should only be used or dispensed by a registered veterinary surgeon and may be administered only under strict veterinary supervision.
• The package leaflet and any other information should draw the attention of the veterinarian to the fact that in certain specified respects, the particulars available concerning the chemical product in question are as yet incomplete.

Before a permit is issued for a veterinary chemical product under the above conditions, you should provide information from scientific literature or pilot studies to justify the proposed dose rate and to support a reasonable expectation of efficacy. For example, studies conducted in another species where a comparable pharmacological profile can be shown may be sufficient to support a conditional dose and a reasonable expectation of efficacy.

You should also provide information demonstrating that the test product is safe when administered to the target species at, at least, the maximum recommended treatment dose and, where practicable, for the maximum duration of therapy.

5. General guidelines for applications for use in minor species or for minor use

You should provide efficacy and safety data of the product under evaluation in the target species to support your application. The means for demonstrating efficacy will be determined on a case-by-case basis. You should make an application to the APVMA for technical assessment early in the development process to ensure that all trials are appropriately designed and will be statistically valid; and that all other recommended guidance for submission of information has been addressed. We will take into consideration the practical limitations of generating data for an infrequently occurring disease. Published literature from acknowledged, ideally peer-reviewed, scientific journals may be used to support part of or the entire efficacy claim.

Veterinary chemical products intended for use under permit in minor species or for minor use must fall within the definition of ‘minor use’ permits (or some other available permit for use) and will be classified under 5 main categories:

• Registered veterinary chemical product supplied for use in a minor species
• Registered veterinary chemical product supplied for a minor use in a major species
• Therapeutic Goods Administration–registered human medicinal product supplied for use in a major or minor species
• Unregistered product containing an approved active constituent supplied for use in a minor species or for a minor use
• Unregistered product containing an unapproved active constituent supplied for use in a minor species or for a minor use

Generally, in all 5 categories the following should be provided:

• Data to characterise the mechanism of action and the known pharmacological (including toxicological) effects of the active substance. Consideration should be given to the pharmacokinetic behaviour of the active substance and the effect of route of administration, formulation and so forth on the pharmacological activity of the test product.
• Data to support the recommended treatment dose, duration of therapy and route of administration.
• Data to demonstrate the safety of the product in the target species to the test product following administration by the proposed route.
• Data to support the efficacy of the product for all proposed indications in the target species.

If adequate information does not exist in the literature, you should demonstrate the efficacy of the product in appropriately designed studies. The type and number of studies to be conducted will depend on the deficiencies in available data. If you choose to conduct new studies to support the efficacy and safety of a product, you can obtain further information from the APVMA data guidelines.

6. Registered veterinary chemical product supplied for use in a minor species (can be referred to as off-label use)

Extrapolation of data from a major to a minor species will be considered where the product is approved for a similar indication in a major species, and where the pharmacology (both in terms of pharmacodynamics and pharmacokinetics) of the test product is likely to be comparable in both species.

Information should be provided to:

• show the practical use of the product in the minor species
• establish if accurate dosing of the product can be achieved
• address concerns about residues.

7. Registered veterinary chemical product supplied for a minor use (can be referred to as off-label use)

In the majority of cases where a registered product is used in a major species to treat a rare condition not listed on the label, the dose rate and route of administration for the proposed minor use indication will be unchanged, and therefore applicants may choose not to submit data. If the dose rate and/or route of administration proposed for the minor use are different to those already approved, similar sets of circumstances as indicated above in the general guidelines for applications for use in minor species or for minor use would likely apply and similar information should be submitted.

8. Therapeutic Goods Administration-registered human medicinal product supplied for use in a minor species or for a minor use

If a human medicine is already registered by Therapeutic Goods Administration, the product will have been assessed for chemistry and manufacture, toxicology and occupational health and safety. In this instance, you should submit information related to the use of the product in the minor species or for the minor use; that is, dosing accuracy, efficacy and safety information as well as residues as appropriate.

9. Unregistered product containing an approved active constituent supplied for use in a minor species or for a minor use

The information that may be submitted in addition to efficacy and safety on target species will depend on the information held by the APVMA on the active constituent. Under such circumstances, you may choose to apply to the APVMA for a technical assessment.

10. Unregistered product containing an unapproved active constituent supplied for use in a minor species or for a minor use

Due to the cost of developing an entirely new veterinary chemical product, it is likely that this category will be encountered rarely. In all such cases, you should provide full efficacy and safety studies.

11. Target animal safety and efficacy studies

You should provide appropriate data to show the safety of the test product to the target species following administration by the proposed route. Whether you choose to submit specific target animal safety studies in minor species will depend on the information available on the safety of the active constituent or product in the minor species or another species (or both). This information may include data from toxicity studies in surrogate laboratory animals, literature reports, pharmacovigilance data, and safety information derived from efficacy studies. For example, if the test product is approved for another species and is known to have a wide margin of safety in that species, field study data demonstrating satisfactory tolerance in the target species following administration of the test product at the recommended treatment dose for the recommended duration of therapy may be considered adequate in lieu of a specific target animal safety study. The safety data should include a copy of scientific articles cited.

Where no data or limited data on the safety profile of the active substance in the target species are available, a basic controlled study demonstrating the safety of the (near-) final formulation in the target species should be provided. In order to demonstrate a margin of safety in the target species, the study should be designed to investigate the safety of the product when it is administered at doses in excess of the recommended treatment dose (for example, three times and five times the proposed dose rate). The applicant should justify the study design proposed. Where safety in breeding animals of another species is demonstrated, applicants may provide valid scientific data in lieu of additional safety data in breeding animals of the target species. However, in the absence of adequate data, a restriction on use in breeding animals (for example, use in accordance with the risk/benefit assessment of a veterinary surgeon) may apply.

Interspecies extrapolation of pre-clinical data to support applications for minor species can be supportive if scientifically justified. You should provide a rationale for the selected treatment regime and duration of therapy. The proposed treatment regime may be justified using one or more of the following:

• Specific dose determination studies
• Pharmacokinetic and pharmacodynamic (for example, minimal inhibitory concentration) data
• Literature data or results of pilot studies or clinical experience reports
• Extrapolation from another species for which the product is registered

You should provide a dose confirmation study and a field trial. Clinical studies should be conducted using the final formulation. In the absence of specific dose determination studies, the efficacy of the product at the recommended dose regime should be demonstrated in an adequate and controlled dose confirmation study in the target species. Dose confirmation studies may not be needed if a field study has been provided and the selected dose is justified

12. Applying for a minor use permit

Applicants should apply for a minor use permit online through the APVMA's Online Services Portal.